RESUMEN

BACKGROUND: Stem-cell-derived therapy is a promising option for tissue regeneration. Human iPSC-derived progenitors of smooth muscle cells (pSMCs) exhibit limited proliferation and differentiation, which minimizes the risk of tumor formation while restoring smooth muscle cells (SMCs). Up to 29% of women suffer from recurrence of vaginal prolapse after prolapse surgery. Therefore, there is a need for therapies that can restore vaginal function. SMCs contribute to vaginal tone and contractility. We sought to examine whether human pSMCs can restore vaginal function in a rat model. METHODS: Female immunocompromised RNU rats were divided into 5 groups: intact controls (n = 12), VSHAM (surgery + saline injection, n = 35), and three cell-injection groups (surgery + cell injection using pSMCs from three patients, n = 14/cell line). The surgery to induce vaginal injury was analogous to prolapse surgery. Menopause was induced by surgical ovariectomy. The vagina, urethra, bladder were harvested 10 weeks after surgery (5 weeks after cell injection). Organ bath myography was performed to evaluate the contractile function of the vagina, and smooth muscle thickness was examined by tissue immunohistochemistry. Collagen I, collagen III, and elastin mRNA and protein expressions in tissues were assessed. RESULTS: Vaginal smooth muscle contractions induced by carbachol and KCl in the cell-injection groups were significantly greater than those in the VSHAM group. Collagen I protein expression in the vagina of the cell-injections groups was significantly higher than in the VSHAM group. Vaginal elastin protein expression was similar between the cell-injection and VSHAM groups. In the urethra, gene expression levels of collagen I, III, and elastin were all significantly greater in the cell-injection groups than in the VSHAM group. Collagen I, III, and elastin protein expression of the urethra did not show a consistent trend between cell-injection groups and the VSHAM group. CONCLUSIONS: Human iPSC-derived pSMCs transplantation appears to be associated with improved contractile function of the surgically injured vagina in a rat model. This is accompanied by changes in extracellular protein expression the vagina and urethra. These observations support further efforts in the translation of pSMCs into a treatment for regenerating the surgically injured vagina in women who suffer recurrent prolapse after surgery.

Asunto(s)

Modelos Animales de Enfermedad , Miocitos del Músculo Liso , Vagina , Animales , Femenino , Ratas , Humanos , Miocitos del Músculo Liso/metabolismo , Trasplante de Células Madre/métodos , Elastina/metabolismo , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Contracción Muscular , Diferenciación Celular

RESUMEN

Background: Stem-cell-derived therapy is a promising option for tissue regeneration. Human iPSC-derived progenitors of smooth muscle cells (pSMCs) have limited proliferation and differentiation, which may minimize the risk of in vivo tumor formation while restoring smooth muscle cell deficiencies. Up to 30 % of women who suffer from recurrence of vaginal prolapse after prolapse surgery are faced with reoperation. Therefore, there is an unmet need for therapies that can restore vaginal tissue function. We hypothesize that human pSMCs can restore vaginal function in a vaginal-injury rat model. Methods: Female immune-compromised RNU rats were divided into 5 groups: intact controls (n=12), VSHAM (surgery + saline injection, n=33), and cell-injection group (surgery + cell injection using three patient pSMCs lines, n=14/cell line). The surgery, similar to what is done in vaginal prolapse surgery, involved ovariectomy, urethrolysis, and vagina injury. The vagina, urethra, bladder dome and trigone were harvested 10 weeks after surgery (5 weeks after injection). Organ bath myography was performed to evaluate the contractile function of vagina, and smooth muscle thickness was examined by tissue immunohistochemistry. Collagen I, collagen III, and elastin mRNA and protein expressions in tissues were assessed. Results: When compared to the VSHAM group, cell-injection groups showed significantly increased vaginal smooth muscle contractions induced by carbachol (groups A and C) and by KCl (group C), and significantly higher collagen I protein expression in the vagina (groups A and B). Elastin mRNA and protein expressions in the vagina did not correlate with injection group. In the urethra, mRNA expressions of collagen I, collagen III, and elastin were all significantly higher in the cell-injection groups compared to the VSHAM group. Collagen I protein expression of the urethra was also higher in the cell-injection group compared to the VSHAM group. Elastin protein expression in the urethra did not correlate with injection group. Conclusions: Human iPSC-derived pSMCs improved contractile function of the post-surgery vagina. Additionally, pSMC injection modulated collagen I, collagen III and elastin mRNA and protein expressions in the vagina and urethra. These findings suggest that pSMCs may be a possible therapy for vaginal prolapse recurrence after surgical intervention.